Treating rhinitis by topically administering an epinastine solution to the nasal mucous membrane

ABSTRACT

A method for treating allergic rhinitis, comprising topically administering to the nasal mucus membrane of a host in need of such treatment a solution comprising: epinastine, optionally in the form of its racemate, its enantiomers, or its pharmacologically acceptable acid addition salts, in a pharmacologically acceptable carrier.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/271,180, filedOct. 15, 2002, which is a continuation of U.S. Ser. No. 09/706,650,filed Nov. 6, 2000, now abandoned, which claims priority to GermanApplication No. 199 54 516.2, filed Nov. 12, 1999, and claims benefit ofU.S. Provisional Application Ser. No. 60/167,771, filed on Nov. 29,1999, each of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to topically administered aqueous solutionscontaining epinastine, optionally in the form of its racemates, itsenantiomers, and optionally in the form of the pharmacologicallyacceptable acid addition salts thereof.

BACKGROUND OF THE INVENTION

Allergic reactions of the eye (hereinafter referred to as ocularallergic reactions) signifies a series of differently defined syndromes.The following are examples of ocular allergic reactions, e.g., seasonalallergic conjunctivitis, perennial allergic conjunctivitis, giant cellconjunctivitis, vernal keratoconjunctivitis, or atopickeratoconjunctivitis. Examples of allergic reactions of the nose(hereinafter referred to as nasal allergic reactions) include seasonalallergic rhinitis and perennial allergic rhinitis, for example.

The immunological mechanism on which ocular and nasal allergic reactionsare based comprises, inter alia, inflammatory processes caused byhistamine. The allergic reactions produced by the release of histamineoccur at an early stage of the ocular and nasal allergic reactionsmentioned above. Moreover, ocular and nasal allergic reactions may bedue to the release of other mast cell mediators as well as toxiceosinophilic granule proteins and enzymes. The influx of neutrophils andeosinophils into the tissue of the ocular conjunctiva and the nasalmucous membrane leads to a late phase reaction, hereinafter referred toas LPR. LPR normally occurs within a period of 3-6 hours after theinitial histamine-mediated allergic reaction. LPR is also characterizedby the occurrence of vasodilation and chemosis and by the swelling ofthe conjunctiva and the nasal mucous membrane.

Whereas histamine-produced allergic reactions can be counteracted byadministering antihistamines, the influx of neutrophils and eosinophilsinto the tissue of the ocular conjunctiva and the nasal mucous membraneremains unaffected by administering pure antihistamines.

PROBLEM OF THE INVENTION

The problem of the present invention is therefore to provide topicallyadministrable solutions which inhibit the influx of neutrophils andeosinophils into the tissue of the ocular conjunctiva and the nasalmucous membrane, thereby reducing or preventing the occurrence of LPRand are therefore characterized by a longer lasting duration ofactivity.

DETAILED DESCRIPTION OF THE INVENTION

It has been found, surprisingly, that topically administrable aqueoussolutions containing epinastine, optionally in the form of its racemate,its enantiomers and possibly in the form of the pharmacologicallyacceptable acid addition salts thereof, may be used to solve the problemon which the invention is based, since they inhibit the influx ofneutrophils and eosinophils into the tissue of the ocular conjunctivaand nasal mucous membrane, thereby reducing or preventing the occurrenceof LPR and are accordingly characterized by a longer lasting duration ofactivity.

The compound epinastine(3-amino-9,13b-dihydro-1H-dibenz-[c,f]imidazol[1,5-a]azepine) and theacid addition salts thereof were described for the first time in GermanPatent Application P 30 08 944.2.

The effect of the topically administered solutions containing epinastineas inhibitors of the influx of eosinophils and neutrophils wasdemonstrated using the so-called passive ocular anaphylaxis model inrats.

DESCRIPTION OF EXPERIMENT

72 hours after the rats have been sensitized by injecting antiserum intothe eyelids of the test animals, a fresh provocation was induced in themby intravenous administration of ovalbumin. Some of the experimentalanimals were pretreated by the administration of solution containingepinastine according to the invention into the conjunctival sac 15minutes before the ovalbumin is administered. Two hours after theadministration of ovalbumin the experimental animals were killed and theconjunctiva was investigated for its content of eosinophils andneutrophils and the mast cell granulation was determined.

RESULTS

The animals pretreated with epinastine solution according to theinvention (0.05-0.5%) had a significantly lower content of eosinophilsin their conjunctiva. The animals pretreated with epinastine solutionaccording to the invention had a significantly lower content oflymphocytes in their conjunctiva (p<0.01). In the animals pretreatedwith epinastine solution according to the invention, a roughly 35%inhibition of mast cell degranulation was determined (p<0.01).

Consequently, the invention relates to topically administered aqueoussolutions containing epinastine, optionally in the form of its racemate,its enantiomers and optionally in the form of the pharmacologicallyacceptable addition salts thereof, in a concentration of 0.005 to 0.5,preferably 0.02 to 0.1, most preferably 0.03 to 0.07 mg/ml of solution.

The abovementioned topically administered aqueous solutions containingepinastine hydrochloride are preferred according to the invention.

Suitable aqueous solvents are physiologically acceptable aqueoussolvents, physiologically acceptable saline solutions being particularlypreferred.

According to the invention, topically administered solutions arepreferably prepared which typically contain 0.005 to 0.5, preferably0.02 to 0.1, most preferably 0.03 to 0.07 mg/ml of epinastine,optionally in the form of its racemate, its enantiomers and optionallyin the form of the pharmacologically acceptable acid addition saltsthereof, as well as physiological saline solutions as the main carriers.The pH of the solutions according to the invention should preferably bemaintained within the range from 6.5 to 7.2 by means of a suitablebuffer system. The preparations may also contain conventional,pharmaceutically acceptable excipients, preservatives, stabilizers,and/or penetration promoters.

The preferred carrier which may be used in the solutions according tothe invention is purified water and preferably a physiological salinesolution.

Without restricting the subject matter of the invention to thefollowing, the excipients which may be used according to the inventioninclude viscosity agents such as polyvinyl alcohol, povidone,hydroxypropylmethylcellulose, poloxamers, carboxymethylcellulose,carbomers, and hydroxyethylcellulose.

Without restricting the subject matter of the invention to thefollowing, the preferred preservatives which may be used in thesolutions according to the invention include benzalkonium chloride,chlorobutanol, thimerosal, phenyl mercury acetate, and phenyl mercurynitrate.

The penetration promoters may be, for example, surfactants, specificorganic solvents such as dimethylsulfoxide and other sulfoxides,dimethylacetamide and pyrrolidone, specific amides of heterocyclicamines, glycols such as propylene glycol, propylene carbonate, oleicacid, alkylamines and derivatives thereof, various cationic, anionic,non-ionogenic, and amphoteric surfactants and the like.

Substances may be added as necessary or as desired in order to adjustthe tonicity of the solution. Such substances include salts andespecially sodium chloride, potassium chloride, mannitol, and glycerolor other suitable physiologically acceptable agents for adjustingtonicity, without restricting the invention to the above.

Various buffers and substances may be used to adjust the pH, providedthat the preparation obtained is physiologically acceptable. Thesebuffers might include acetate buffer, citrate buffer, phosphate bufferand borate buffer.

Similarly, physiologically acceptable antioxidants which may be usedaccording to the invention include sodium metabisulphite, sodiumthiosulphate, acetylcysteine, butylated hydroxyanisole, and butylatedhydroxytoluene, without restricting the invention to this list.

Other carrier components which may be incorporated in the solutionsaccording to the invention are chelating agents. The preferred chelatingagent is disodium edetate (Na-EDTA), although other chelating agents mayalso be used instead of or in conjunction with disodium edetate.

The abovementioned topically administered aqueous solutions according tothe invention may be applied either to the conjunctiva or to the nasalmucous membrane. Solutions for ophthalmic use are of equal importance tosolutions for nasal application for the purposes of the presentinvention.

The invention relates not only to the solutions according to theinvention mentioned hereinbefore but also to the use of theabovementioned topically administered aqueous solutions for inhibitingthe influx of neutrophils and eosinophils into the tissue of the ocularconjunctiva or the tissue of the nasal mucous membrane.

The present invention also relates to the use of epinastine, optionallyin the form of its racemate, its enantiomers and optionally in the formof the pharmacologically acceptable acid addition salts thereof, forproducing the topically administered aqueous solutions according to theinvention for treating disorders of the ocular conjunctiva or the nasalmucous membranes in which there is therapeutic value in inhibiting theinflux of neutrophils and eosinophils into the tissue of the ocularconjunctiva or the nasal mucous membrane in allergic reactions.

The abovementioned use for inhibiting LPR is preferred, whilst it isparticularly preferable to use the preparation to treat the diseaseslisted at the beginning.

The Examples shown in Table 1 illustrate the invention withoutrestricting it. TABLE 1 Solution 1 Solution 2 Solution 3 Solution 4Solution 5 Solution 6 Solution 7 0.05% 0.01% 0.05% 0.10% 0.01% 0.05%0.10% [g/100 ml] [g/100 ml] [g/100 ml] [g/100 ml] [g/100 ml] [g/100 ml][g/100 ml] Epinastine hydrochloride 0.0500 0.0100 0.0500 0.1000 0.01000.0500 0.1000 Na-EDTA 0.0500 0.0500 0.0500 0.0500 — — — Sodium chloride0.5000 0.5000 0.5000 0.5000 0.5000 0.5000 0.5000 Sodium dihydrogenphosphate 0.7800 0.7800 0.7800 0.7800 0.4100 0.4100 0.4100 dihydrateBenzalkonium chloride 0.0101 0.0101 0.0101 0.0101 0.0101 0.0101 0.0101Sodium hydroxide 0.0001 0.0001 0.0001 0.0001 — — — Sodium dihydrogenphosphate — — — — 0.6500 0.6500 0.6500 dihydrate Hydroxyethylcellulose —— — — 0.1000 0.1000 0.1000 Water 99.4198 99.4598 99.4198 99.3698 99.074999.0349 99.9849 100.8100 100.8100 100.8100 100.8100 100.7550 100.7550100.7550

1. A method for treating late phase reactions of allergic rhinitis bytopically administering to the nasal mucous membrane of a host in needof such treatment a solution comprising: (a) epinastine, optionally inthe form of its racemate, its enantiomers, or its pharmacologicallyacceptable acid addition salts, in a concentration of 0.005 to 0.5 mg/mlof solution; (b) water or physiologically acceptable saline; and (c) apreservative, wherein the pH is adjusted to between 6.5 and 7.2 by meansof a physiologically acceptable buffer, and optionally also includingone or more chelating agents, viscosity agents, penetration promoters,antioxidants, or substances to adjust the tonicity of the solution. 2.The method according to claim 1, wherein the concentration of epinastinein the solution is 0.02 to 0.1 mg/ml of solution.
 3. The methodaccording to claim 2, wherein the concentration of epinastine in thesolution is 0.03 to 0.07 mg/ml of solution.
 4. The method according toclaim 1, wherein the solution comprises epinastine hydrochloride.
 5. Themethod according to claim 1, wherein the preservative is selected fromthe group consisting of: benzalkonium chloride, chlorobutanol,thimerosal, phenyl mercury acetate, and phenyl mercury nitrate.
 6. Themethod according to claim 4, wherein the solution further comprises aviscosity agent.
 7. The method according to claim 6, wherein theviscosity agent is selected from the group consisting of: polyvinylalcohol, povidone, hydroxypropylmethylcellulose, poloxamers,carboxymethylcellulose, carbomers, and hydroxyethylcellulose.
 8. Themethod according to claim 4, wherein the solution further comprises apenetration promoter.
 9. The method according to claim 8, wherein thepenetration promoter is selected from the group consisting of: cationic,anionic, non-ionogenic, and amphoteric surfactants; dimethylsulfoxideand other sulfoxides; dimethylacetamide and pyrrolidone; amides ofheterocyclic amines; glycols; propylene carbonate; oleic acid; andalkylamines and derivatives thereof.
 10. The method according to claim1, wherein the solution further comprises a substance to adjust thetonicity of the solution selected from the group consisting of: sodiumchloride, potassium chloride, mannitol, and glycerol.
 11. The methodaccording to claim 1, wherein the solution further comprises a bufferselected from the group consisting of: acetate buffer, citrate buffer,phosphate buffer, and borate buffer.
 12. The method according to claim1, wherein the solution further comprises an antioxidant selected fromthe group consisting of: sodium metabisulphite, sodium thiosulphate,acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.13. The method according to claim 1, wherein the solution furthercomprises the chelating agent disodium edetate.
 14. The method accordingto claim 1, wherein the solution comprises epinastine hydrochloride,water, sodium chloride, sodium hydrogen phosphate dihydrate,benzalkonium chloride, hydroxyethylcellulose, and optionally sodium EDTAand sodium hydroxide.
 15. A method for treating late phase reactions ofallergic rhinitis by topically administering to the nasal mucousmembrane of a host in need of such treatment a solution comprising: (a)epinastine, optionally in the form of its racemate, its enantiomers, orits pharmacologically acceptable acid addition salts, in a concentrationof 0.02 to 0.5 mg/ml of solution; (b) water or physiologicallyacceptable saline; and (c) a preservative, wherein the pH is adjusted tobetween 6.5 and 7.2 by means of a physiologically acceptable buffer, andoptionally also including one or more chelating agents, viscosityagents, penetration promoters, antioxidants, or substances to adjust thetonicity of the solution.
 16. A method for treating late phase reactionsof allergic rhinitis by topically administering to the nasal mucousmembrane of a host in need of such treatment a solution comprising: (a)epinastine, optionally in the form of its racemate, its enantiomers, orits pharmacologically acceptable acid addition salts, in a concentrationof 0.005 to 1.0 mg/ml of solution; (b) water or physiologicallyacceptable saline; and (c) a preservative, wherein the pH is adjusted tobetween 6.5 and 7.2 by means of a physiologically acceptable buffer, andoptionally also including one or more chelating agents, viscosityagents, penetration promoters, antioxidants, or substances to adjust thetonicity of the solution.
 17. A method for treating allergic rhinitis bytopically administering to the nasal mucous membrane of a host in needof such treatment a solution comprising: (a) epinastine, optionally inthe form of its racemate, its enantiomers, or its pharmacologicallyacceptable acid addition salts, in a concentration of 0.005 to 0.5 mg/mlof solution; (b) water or physiologically acceptable saline; and (c) apreservative, wherein the pH is adjusted to between 6.5 and 7.2 by meansof a physiologically acceptable buffer, and optionally also includingone or more chelating agents, viscosity agents, penetration promoters,antioxidants, or substances to adjust the tonicity of the solution. 18.The method according to claim 17, wherein the concentration ofepinastine in the solution is 0.02 to 0.1 mg/ml of solution.
 19. Themethod according to claim 18, wherein the concentration of epinastine inthe solution is 0.03 to 0.07 mg/ml of solution.
 20. The method accordingto claim 17, wherein the solution comprises epinastine hydrochloride.21. The method according to claim 17, wherein the preservative isselected from the group consisting of: benzalkonium chloride,chlorobutanol, thimerosal, phenyl mercury acetate, and phenyl mercurynitrate.
 22. The method according to claim 20, wherein the solutionfurther comprises a viscosity agent.
 23. The method according to claim22, wherein the viscosity agent is selected from the group consistingof: polyvinyl alcohol, povidone, hydroxypropylmethylcellulose,poloxamers, carboxymethylcellulose, carbomers, andhydroxyethylcellulose.
 24. The method according to claim 20, wherein thesolution further comprises a penetration promoter.
 25. The methodaccording to claim 24, wherein the penetration promoter is selected fromthe group consisting of: cationic, anionic, non-ionogenic, andamphoteric surfactants; dimethylsulfoxide and other sulfoxides;dimethylacetamide and pyrrolidone; amides of heterocyclic amines;glycols; propylene carbonate; oleic acid; and alkylamines andderivatives thereof.
 26. The method according to claim 17, wherein thesolution further comprises a substance to adjust the tonicity of thesolution selected from the group consisting of: sodium chloride,potassium chloride, mannitol, and glycerol.
 27. The method according toclaim 17, wherein the solution further comprises a buffer selected fromthe group consisting of: acetate buffer, citrate buffer, phosphatebuffer, and borate buffer.
 28. The method according to claim 17, whereinthe solution further comprises an antioxidant selected from the groupconsisting of: sodium metabisulphite, sodium thiosulphate,acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.29. The method according to claim 17, wherein the solution furthercomprises the chelating agent disodium edetate.
 30. The method accordingto claim 17, wherein the solution comprises epinastine hydrochloride,water, sodium chloride, sodium hydrogen phosphate dihydrate,benzalkonium chloride, hydroxyethylcellulose, and optionally sodium EDTAand sodium hydroxide.
 31. A method for treating allergic rhinitis bytopically administering to the nasal mucus membrane of a host in need ofsuch treatment a solution comprising: (a) epinastine, optionally in theform of its racemate, its enantiomers, or its pharmacologicallyacceptable acid addition salts, in a concentration of 0.005 to 1.0 mg/mlof solution; (b) water or physiologically acceptable saline; and (c) apreservative, wherein the pH is adjusted to between 6.5 and 7.2 by meansof a physiologically acceptable buffer, and optionally also includingone or more chelating agents, viscosity agents, penetration promoters,antioxidants, or substances to adjust the tonicity of the solution. 32.A method for treating allergic rhinitis, comprising topicallyadministering to the nasal mucus membrane of a host in need of suchtreatment a solution comprising: epinastine, optionally in the form ofits racemate, its enantiomers, or its pharmacologically acceptable acidaddition salts, in a pharmacologically acceptable carrier.
 33. Themethod according to claim 32, wherein the solution comprises: (a)epinastine, optionally in the form of its racemate, its enantiomers, orits pharmacologically acceptable acid addition salts, in a concentrationof 0.005 to 0.5 mg/ml of solution; (b) physiologically acceptablesaline; and (c) a preservative, wherein the pH is adjusted to between6.5 and 7.2 by means of a physiologically acceptable buffer, andoptionally also including one or more chelating agents, viscosityagents, penetration promoters, antioxidants, or substances to adjust thetonicity of the solution.
 34. The method according to claim 33, whereinthe concentration of epinastine in the solution is 0.02 to 0.1 mg/ml ofsolution.
 35. The method according to claim 34, wherein theconcentration of epinastine in the solution is 0.03 to 0.07 mg/ml ofsolution.
 36. The method according to claim 32, wherein the solutioncomprises epinastine hydrochloride.
 37. The method according to claim36, wherein the solution further comprises a viscosity agent.
 38. Themethod according to claim 36, wherein the solution further comprises apenetration promoter.
 39. The method according to claim 36, wherein thesolution further comprises a substance to adjust the tonicity of thesolution selected from the group consisting of: sodium chloride,potassium chloride, mannitol, and glycerol.
 40. The method according toclaim 36, wherein the solution further comprises a buffer selected fromthe group consisting of: acetate buffer, citrate buffer, phosphatebuffer, and borate buffer.
 41. The method according to claim 36, whereinthe solution further comprises an antioxidant selected from the groupconsisting of: sodium metabisulphite, sodium thiosulphate,acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.42. The method according to claim 36, wherein the solution furthercomprises the chelating agent disodium edetate.
 43. The method accordingto claim 36, wherein the solution comprises epinastine hydrochloride,water, sodium chloride, sodium hydrogen phosphate dihydrate,benzalkonium chloride, hydroxyethylcellulose, and optionally sodium EDTAand sodium hydroxide.
 44. A method for treating allergic rhinitiscomprising: (a) identifying a host suffering from or at risk forallergic rhinitis; and (b) topically administering to the nasal mucusmembrane of the host a solution comprising: epinastine, optionally inthe form of its racemate, its enantiomers, or its pharmacologicallyacceptable acid addition salts, in a pharmacologically acceptablecarrier.
 45. The method according to claim 44, wherein the solutioncomprises: (a) epinastine, optionally in the form of its racemate, itsenantiomers, or its pharmacologically acceptable acid addition salts, ina concentration of 0.005 to 0.5 mg/ml of solution; (b) water orphysiologically acceptable saline; and (c) a preservative, wherein thepH is adjusted to between 6.5 and 7.2 by means of a physiologicallyacceptable buffer, and optionally also including one or more chelatingagents, viscosity agents, penetration promoters, antioxidants, orsubstances to adjust the tonicity of the solution
 46. The methodaccording to claim 45, wherein the concentration of epinastine in thesolution is 0.02 to 0.1 mg/ml of solution.
 47. The method according toclaim 46, wherein the concentration of epinastine in the solution is0.03 to 0.07 mg/ml of solution.
 48. The method according to claim 44,wherein the solution comprises epinastine hydrochloride.
 49. The methodaccording to claim 48, wherein the solution further comprises aviscosity agent.
 50. The method according to claim 48, wherein thesolution further comprises a penetration promoter.
 51. The methodaccording to claim 48, wherein the solution further comprises asubstance to adjust the tonicity of the solution selected from the groupconsisting of: sodium chloride, potassium chloride, mannitol, andglycerol.
 52. The method according to claim 48, wherein the solutionfurther comprises a buffer selected from the group consisting of:acetate buffer, citrate buffer, phosphate buffer, and borate buffer. 53.The method according to claim 48, wherein the solution further comprisesan antioxidant selected from the group consisting of: sodiummetabisulphite, sodium thiosulphate, acetylcysteine, butylatedhydroxyanisole, and butylated hydroxytoluene.
 54. The method accordingto claim 48, wherein the solution further comprises the chelating agentdisodium edetate.
 55. The method according to claim 48, wherein thesolution comprises epinastine hydrochloride, water, sodium chloride,sodium hydrogen phosphate dihydrate, benzalkonium chloride,hydroxyethylcellulose, and optionally sodium EDTA and sodium hydroxide.